Oxygen is supplied to the cells by the blood and most cellular energy production is tightly coupled to oxygen. Whenever the blood flow to an organ is interrupted, a state of ischemia exists. During ischemia, cellular ATP will be consumed and usually cannot adequately be replenished in the absence of a supply of oxygen. Ischemia can exist for only a portion of an organ when the blockage of the blood supply to the organ is not total. In addition to total ischemia, or no blood flow, there are intermediate degrees of ischemia.
Significant ischemia occurs in stroke and during most cases of open heart-surgery, all episodes of coronary occlusion or heart attack, all cases of organ transplantation, certain procedures such as liver shunt operations and a variety of other situations in which either significant stress or a period of shock has compromised the functioning of one or more organs of the body. In all of these situations, cellular energy metabolism is impaired, and its restoration is critical to the recovery of organ function.
For example, stroke, or cerebrovascular disease, is the name for several disorders that occur within seconds or minutes after the blood supply to the brain is disturbed. Stroke is the third leading cause of death in developed countries. Approximately 550,000 Americans suffer a stroke each year; one fourth of them die and half of the survivors have residual disabilities, including paralysis of face, extremities, speech disorders, loss of bladder function, inability to swallow or dementia. Stroke is the principal cause of severe disability, often requiring institutionalization of stroke survivors at a total cost in the U.S. of $20 to 30 billion dollars per year. Stroke is more likely to occur in the elderly, and the risk doubles each decade after age 35 years. Five percent of the population older than 65 years has had a stroke.
Symptoms of stroke may progress or fluctuate during the first day or two after onset; this is called evolution. When no further deterioration occurs, the condition is considered to be a completed stroke. The only warning signal that suggests susceptibility to a stroke is a transient ischemic attack (TIA).
Strokes are characterized by the location and type of disturbance. The most common is a deficient supply of blood through an artery (ischemia). About 84% of strokes (about 400,000 per year in the U.S.) result from occlusion of cerebral arteries by blood clots. Ischemic cell damage follows rapidly upon interruption of the blood supply downstream from the clot. The remaining 16% of strokes are the result of intracerebral or subarachnoid hemorrhage. While hemorrhage induces other injurious events, ischemia resulting from the “short circuited” blood flow is still a significant factor in neuronal damage from hemorrhagic strokes.
Cell death occurs rapidly in the core region of a stroke, where blood flow is reduced to about 20% of normal. However, there is a larger area of potential injury, called the ischemic penumbra, where blood flow is reduced to a lesser extent. Cells in this region are endangered, but may not be irreversibly damaged. It is this penumbral area wherein neuroprotective agents may have their most beneficial effects in preventing cell damage and death due to ischemia and thereby reducing the incidence of long term disabilities.
Pharmacological intervention into the stroke process has not been successful. For example, studies evaluating the effectiveness of corticosteroids in the setting of head injury or global or focal brain ischemia have demonstrated either no improvement or a worsening of neurological outcome. See, for example, C. T. Wass et al., Anesthesiology, 84, 644 (1996) and references cited therein. A study of stroke patients treated primarily with dexamethasone or methylprednisolone showed no significant difference in outcome between steroid and non-steroid treated patients. J. DeReuck et al., Eur. Neurol., 28, 70 (1988). Chopp et al. have disclosed the use of progestins to treat stroke using stroke models in animals. (See U.S. Pat. No. 6,245,757.)
Due to the lack of available pharmacotherapeutic agents, a significant percentage of the population subject to stroke or its aftereffects are poorly managed. None of the drugs presently available are capable of preventing damage due to stroke and most, such as anticoagulants, which can be shown to speed clot dissolution and hasten reperfusion if given within three hours of the onset of ischemia, have disturbing side effects. Anticoagulants can in fact be fatal if used inappropriately, e.g., for treating a hemorrhagic stroke. Clearly, current therapy has failed to “seize control” of this debilitating pathology.
Human umbilical cord blood (HUCB) has emerged as an alternative stem-cell source for reconstituting the bone marrow and immune systems of patients treated with myeloablative chemotherapy or radiation. See, e.g., J. N. Barker et al., Nature Revs., 3, 562 (2003). The presence of mature and primitive hematopoietic progenitor cells in umbilical cord blood was demonstrated by Knudtzon, Blood, 43, 357 (1974) and Nakahata and Ogawa, J. Clin. Invest., 70, 1324 (1982), respectively. Experimental and clinical evidence demonstrating the feasibility of using UCB in lieu of bone marrow transplantation was later provided by Broxmeyer et al., Proc. Natl. Acad. Sci. USA, 86, 3828 (1989) and Gluckman et al., N. Engl. J. Med., 321, 1174 (1989). The presence of CD34+ progenitor cells and their ability to differentiate along a hematopoietic lineage is well documented.
P. R. Sandberg et al., Neurosci. Abstr., 27, 632 (2001) have investigated whether intravenously infused human umbilical cord blood cells (HUCBC) enter the brain, survive, and improve neurological functional recovery after stroke or traumatic brain injury (TBI) in rats. In the experimental groups, HUCBC were injected into the tail vein at least 24 hours after stroke or TBI. Behavioral impairments were reported to be significantly improved as early as 14 days in both TBI and stroke animals, compared to controls. Injected cells entered brain and migrated into the parenchyma of the injured brain. The number of MAB1281 positive cells in the ipsi-lateral hemisphere were at least 3 times greater than in the contralateral side. Some of the cells expressed the neuronal markers, the astrocytic marker GFAP, and the endothelial cell marker FVIII. Sandberg et al. reported significant HUCBC in vivo migration to the brain tissue 24 hrs after injury, when compared to normal tissue. See also, P. R. Sandberg et al., J. Neurochemistry, 81(5), 83 (2002); D. Lu et al., Cell Transplantation, 11, 275 (2002); J. Chen et al., Stroke, 32, 2682 (2001). However, the factors and/or cellular populations that may ameliorate the effects of stroke and traumatic brain injury remain to be characterized.